Associations between food restriction and substance abuse have been observed in clinical populations, adults, adolescents, and children. Preliminary reports suggest that weight loss following gastric bypass surgery may also increase substance abuse risk. This laboratory has demonstrated that the rewarding effects of abused drugs are greater in chronically food-restricted (FR) than ad libitum fed (AL) rats. We have also shown that FR increases acquisition and expression of cocaine conditioned place preference (CPP); moreover, our studies show an enhancing effect of FR on expression of a cocaine CPP acquired during a prior AL fed state. These data are the first evidence that FR increases the incentive effects of a drug-paired context, with enhancing effects on at least two behavioral processes that increase vulnerability to substance abuse. Our recent mechanistic studies demonstrate that FR increases: (i) the abundance of glutamatergic AMPA receptor GluA1 subunits in nucleus accumbens (NAc) postsynaptic density (PSD), (ii) psychostimulant- and sucrose-induced phosphorylation of GluA1 on Ser845, and (iii) psychostimulant- and sucrose-induced delivery of GluA1 and GluA2 to the NAc PSD. These findings are important because AMPARs mediate dynamic tuning of synaptic transmission as well as enduring forms of synaptic plasticity. Initial pharmacological results confirm that the enhanced rewarding effects of psychostimulants in FR rats are mediated by GluA1-containing/GluA2-lacking AMPA receptors in NAc shell, and the enhanced conditioned hyperactivity of FR rats anticipating reward is mediated by AMPARs in NAc core. Thus, the overarching hypothesis to be tested in the proposed research is that FR facilitates trafficking of AMPARs to the NAc postsynaptic density and thereby enhances the rewarding effects of psychostimulants and environments associated with them. Experiments of Aim 1 will therefore combine biochemical, pharmacological, and behavioral assays to assess whether increased synaptic abundance of GluA2-lacking AMPA receptors in NAc subregions mediate the enhanced behavioral responsiveness of FR rats to d-amphetamine, cocaine, and environments that have been paired with them. Experiments of Aim 2 will determine whether acute exposure to psychostimulants and associated environments rapidly deliver AMPA receptors to the NAc postsynaptic density with a greater effect in FR relative to AL rats; results will guide follow-up experiments in which NAc microinjection of a peptide, viral vector, and kinase inhibitor that block AMPA receptor trafficking are used to reverse the enhancing effect of FR on psychostimulant reward and acquisition of psychostimulant-conditioned behavior. Experiments of Aim 3 will determine the role of a likely regulatory factor linking effects of drug abuse and diet, which is corticosterone. It is expected that understanding these neuroadaptations and their recruitment by drugs of abuse will illuminate risk factors and crossover therapies for drug addiction and eating disorders. Among the public health benefits will be recognition of and methods for mitigating the pathogenic potential of neuroplastic changes that accompany weight loss dieting and, pending additional data, gastric bypass surgery.